Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease

Boyett, Mark R.; Yanni, Joseph; Tellez, James O.; Bucchi, Annalisa; Mesirca, Pietro; Cai, Xue; Logantha, Sunil Jit R. J.; Wilson, Claire; Anderson, Cali; Ariyaratnam, Jonathan; Stuart, Luke; Nakao, Shin-ichi; Allah, Eman S.H. Abd; Jones, Sandra A.; Lancaster, Matthew K.; Stephenson, Robert S.; Chandler, Natalie; Smith, Matthew; Bussey, Carol T.; Monfredi, Oliver; Morris, Gwilym M.; Billeter, Rudi; Mangoni, Matteo E.; Zhang, Henggui; Hart, George; D’Souza, Alicia

doi:10.1016/j.pbiomolbio.2021.06.008

Cited by 21 publications

(9 citation statements)

References 236 publications

(310 reference statements)

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“…It was identifiable by being node‐like in appearance, by being relatively rich in collagen and by a low expression of cardiac troponin I (Figure 11d ). In addition, Hcn4 which is a key marker of the conduction system (Boyett et al, 2021 ), was expressed in a subset of the myocardium with a low expression of troponin I (Figure 11d ) which is another characteristic of conduction tissue (Sizarov et al, 2011 ). This presumed sinus node was small, approximately 100 μm wide and 500 μm dorso‐ventrally long in all three investigated specimens.…”

Section: Resultsmentioning

confidence: 99%

“…Given the extremely high heart rates of shrews, one could presume an unusual cardiac conduction system. The cardiac conduction system has been identified on the basis of histological characters such as weak stain and richness in collagen (Davies, 1942 ; Ho et al, 2003 ) and on the presence of the funny current channel, Hcn4 (Boyett et al, 2021 ; Sizarov et al, 2011 ). We show in the shrew the presence of myocardium that is insulated by collagen and that expresses Hcn4 where a mammal sinus node and His bundle would be expected.…”

Section: Discussionmentioning

confidence: 99%

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Anatomy of the heart with the highest heart rate

2022

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Shrews are eutherian insectivore mammals that can be tiny. Adult Eurasian least shrew (Sorex minutissimus) and Eurasian pygmy shrews (Sorex minutus), which we study in this report, only weigh a few grams.They occupy therefore the lower extreme of the seven orders of magnitude that mammals range in size. Because not much is known of their cardiac anatomy (Rowlatt, 1990;Vornanen, 1989), it is not clear whether typical traits of mammal hearts scale to such miniscule sizes. Valves and chamber wall thicknesses would be predicted to scale linearly to cavity size according to the law of Laplace (Jensen, 2021;Seymour & Blaylock, 2000) and typical proportions of valves, walls, and cavities might well scale to shrews. In contrast, resistance to blood flow is inversely related to vessel diameter raised to the power of four according to the Hagen-Poiseuille equation and very small arteries and veins in the shrew may impose high resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anatomy of the heart with the highest heart rate

2022

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“…Given the numerous mechanisms that interact to produce SA nodal pacemaking at the cellular level [ 49 , 50 ], it was not especially surprising that heterogeneity in ionic current properties caused a percentage of cells to cease beating spontaneously. Although it seems reasonable to ask whether this behavior is realistic or an artifact of the modeling, recent studies strongly suggest that dormant cells do indeed exist, both in isolated cell studies and within intact SA nodal tissue.…”

Section: Discussionmentioning

confidence: 99%

Coupling and heterogeneity modulate pacemaking capability in healthy and diseased two-dimensional sinoatrial node tissue models

et al. 2022

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Both experimental and modeling studies have attempted to determine mechanisms by which a small anatomical region, such as the sinoatrial node (SAN), can robustly drive electrical activity in the human heart. However, despite many advances from prior research, important questions remain unanswered. This study aimed to investigate, through mathematical modeling, the roles of intercellular coupling and cellular heterogeneity in synchronization and pacemaking within the healthy and diseased SAN. In a multicellular computational model of a monolayer of either human or rabbit SAN cells, simulations revealed that heterogenous cells synchronize their discharge frequency into a unique beating rhythm across a wide range of heterogeneity and intercellular coupling values. However, an unanticipated behavior appeared under pathological conditions where perturbation of ionic currents led to reduced excitability. Under these conditions, an intermediate range of intercellular coupling (900–4000 MΩ) was beneficial to SAN automaticity, enabling a very small portion of tissue (3.4%) to drive propagation, with propagation failure occurring at both lower and higher resistances. This protective effect of intercellular coupling and heterogeneity, seen in both human and rabbit tissues, highlights the remarkable resilience of the SAN. Overall, the model presented in this work allowed insight into how spontaneous beating of the SAN tissue may be preserved in the face of perturbations that can cause individual cells to lose automaticity. The simulations suggest that certain degrees of gap junctional coupling protect the SAN from ionic perturbations that can be caused by drugs or mutations.

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“…In the sinus node, evidence suggests dysfunction and downregulation of I f in HF [9,10,162,163] which may cause bradyarrhythmia in certain situations. In contrast, in the ventricle, I f is upregulated (Figure 9) [164][165][166] which was attributed to enhanced mRNA and protein expressions of HNC2 and HCN4 channels in the failing human ventricle [167].…”

Section: Changes Of the Pacemaker Current (I F ) In Hfmentioning

confidence: 99%

Arrhythmogenic Remodeling in the Failing Heart

Husti

Varró

Baczkó

2021

Cells

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Chronic heart failure is a clinical syndrome with multiple etiologies, associated with significant morbidity and mortality. Cardiac arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, are common in heart failure. A number of cardiac diseases including heart failure alter the expression and regulation of ion channels and transporters leading to arrhythmogenic electrical remodeling. Myocardial hypertrophy, fibrosis and scar formation are key elements of arrhythmogenic structural remodeling in heart failure. In this article, the mechanisms responsible for increased arrhythmia susceptibility as well as the underlying changes in ion channel, transporter expression and function as well as alterations in calcium handling in heart failure are discussed. Understanding the mechanisms of arrhythmogenic remodeling is key to improving arrhythmia management and the prevention of sudden cardiac death in patients with heart failure.

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Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease

Cited by 21 publications

References 236 publications

Anatomy of the heart with the highest heart rate

Anatomy of the heart with the highest heart rate

Coupling and heterogeneity modulate pacemaking capability in healthy and diseased two-dimensional sinoatrial node tissue models

Arrhythmogenic Remodeling in the Failing Heart

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